SGC - Structural Biology and Human Health: A New Approach to Publishing Structural Biology Results

Abstract

Since its advent, structural biology has played a major role in the understanding of biological processes at the molecular level. This, in turn, has enabled the progression and development of several fields in biological sciences. As a consequence there has been a continuing demand for faster and more cost-effective determination of protein structures and their in-depth functional, mechanistic and biological analysis. The lack of a well-established process historically meant that structures were been solved in a case-by-case manner, with academic researchers establishing specific protocols over a relatively long period of time that are difficult to implement or inappropriate for high-throughput approaches. As the sequencing of the human genome was completed the gap between known genes and solved protein structures became wider. As a result concerted and systematic technology-driven ‘structural genomics’ (SG) efforts to solve protein structures in a high throughput manner were begun (for thorough reviews see [1], [2]). First formalised in 1998 [3]–[5], several major SG efforts were subsequently started such as the NIH-funded Protein Structure Initiative (PSI; http://www.nigms.nih.gov/Initiatives/PSI), European initiatives ‘The Protein Structure Factory (PSF; http://www.proteinstrukturfabrik.de) and ‘Structural Proteomics in Europe (SPINE; http://www.spineurope.org) and Japanese Protein 3000 and RIKEN Structural Genomics/Proteomics programs (http://protein.gsc.riken.jp). The majority of these early programmes were tasked with exploring the breadth of the protein structural universe by focussing on prokaryotic targets whilst driving novel structural biology technology for a high-throughput environment [1], [6]. New avenues have been opened by the availability of detailed structural descriptions of proteins and enzymes involved in the normal (or abnormal) functioning of the human body and associated pathogens. In particular, this information provides a better understanding of the basis by which different proteins achieve selectivity and specific binding to their cognate ligands and drugs [1]. Indeed, several marketed drugs in recent years have been developed using structure-based methods, targeting a wide range of disease such as AIDS, leukaemia, cancers and venous thromboembolic events [1], [7]–[10]. Despite these successes, determining the structures of human proteins in a high-throughput manner was seen to be technically challenging relative to those of less complex organisms (e.g. prokaryotes), where issues such as the lack of solubility of expressed proteins in simple bacterial systems pose major bottlenecks to scaling the structure determination process [11]. The SGC (http://www.thesgc.org) was created in 2003 as a response to this challenge. The SGC is a not-for-profit organisation that aims to solve the three dimensional structures of proteins of medical relevance and place them into the public domain without encumbrance or restriction. The SGC has adopted a protein-family based approach whereby protein targets are chosen from discrete and medically-relevant human protein families. This approach ensures that comparative analysis and “blanket” methods can be applied to members of same family [11]. The SGC is driving the concept of “open-source science” to enable drug discovery by promoting pre-competitive structural biology and medicinal chemistry. This is achieved by combining academic and industrial efforts to create open-access chemical and clinical probes [12]–[14] which might be used in a pre-competitive manner for target validation purposes, for example. Since the production phase of the SGC began in 2004, we have released the coordinates of over 800 protein structures related to several diseases and metabolic disorders into the public domain of which over 700 are novel and unique. Whilst the SGC focuses primarily on human targets, we also pursue the structure determination of proteins from parasitic organisms associated with neglected diseases, such as malaria and toxoplasmosis. We have deposited more than 70 of these structures into the public domain. These structures are providing a significant impact with the SGC providing 61% of publicly available apicomplexan structures. The SGC has also developed new protocols and methods that are now widely used [15]–[18] and is developing chemical probes [19] and small molecules in areas such as human epigenetics and human protein kinases, to be placed in the public domain [1] as part of the ‘open-source’ science approach. In this PLoS ONE Collection we present articles covering the structure determination of a number of targets by the SGC along with additional work carried out to further characterise these proteins. Since SG data is intrinsically heterogeneous and not always accessible to non-specialists, all the articles from this collection are available also as an enhanced version using our interactive visualisation platform – known as iSee – which allows the reader to interact and manipulate the 3D scenes prepared by the authors to highlight and support information given in the main text of the article [20].